HIV-Associated Neurocognitive Disorder (HAND) continues to affect ~50% of HIV(+) patients despite widespread implementation of antiretroviral therapy (ART) and successful viral suppression. Several risk factors including older age, low nadir CD4+ cell count, metabolic syndrome, depression and hepatitis C co-infection associate with HAND. Early interventions and complete viral suppression are most likely to improve neurocognitive (NC) prognosis; the Mind Exchange Program recommends consideration of risk factors for diagnosis and treatment within the first six months. Many of the mechanisms implicated in HAND persistence, including unremitting CNS viral replication, age-related pathologies, comorbidities (e.g., drug abuse, ART-associated toxicities) can induce the unfolded protein response (UPR), which results in activation of one or more of the 3 initiators, PERK, ATF6, and IRE1?, when cellular stressors disrupt their binding to the chaperone, binding protein (BiP), with wide ranging consequences. Most pertinent here is PERK-mediated phosphorylation of eukaryotic translation initiation factor 2? (eIF2?) slows global translation, while selectively enhancing translation of a subset of genes including the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Chronic and/or sustained UPR activation may have detrimental outcomes, supported by multiple studies. Consistently, UPR is implicated in several neurodegenerative diseases, including Alzheimer and Parkinson. We previously showed UPR activation in HAND prefrontal cortex. Based on multiple lines of evidence from in vitro and in vivo models of HIV-induced neurodegeneration, suggesting that the dysregulation of the PERK arm of the UPR pathway may be contributing to HIV- as well as antiretroviral-mediated neurodegenerative processes, we propose a role for PERK dysregulation as a mechanism for the continuing neuronal perturbations still observed in HAND patients despite ART?s success. We propose that PERK activation contributes to HAND development, and a genetic variant of PERK with increased activity is a predictive risk factor for HAND. In this application, we will examine whether a protein-coding PERK haplotype resulting from three single nucleotide polymorphisms (SNPs), which may confer increased kinase activity, may underlie the alteration/s of PERK?s protein function and/or changes in its amount. We will determine: 1) the mechanisms of PERK-mediated neurotoxicity in vitro, 2) the mechanisms of PERK-mediated neuronal injury in a preclinical rodent model of HIV-induced synaptic damage, gliosis and behavioral/cognitive deficits, and 3) the associations between PERK genetic haplotype and/or expression with HAND risk in human adults.